TEMPORAL RELATIONSHIP BETWEEN SYNAPTIC ACTIVITY AND ABETA AGGREGATION

突触活动与 ABETA 聚合之间的时间关系

• 批准号: 8566773
• 负责人: John R Cirrito
• 金额: $ 21.76万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8566773
• 关键词: APP-PS1; Affect; Age-Years; Alzheimer' s Disease; Amino Acids; Amyloid; Animal Model; Animals; Antibodies; Area; Behavioral Symptoms; Biological Markers; Brain; Brain region; Coupled; Data; Detection; Development; Disease Progression; Electrochemistry; Electrodes; Electrons; Endocytosis; Endosomes; Event; Exclusion; Extracellular Space; Frequencies; Generations; Goals; Hippocampus (Brain); Human; In Vitro; Individual; Intercellular Fluid; Kinetics; Lead; Length; Life; Link; Location; Measures; Methodology; Methods; Microdialysis; Molecular Conformation; Mus; Neurobehavioral Manifestations; Neurons; Onset of illness; Pathogenesis; Peptides; Positioning Attribute; Presynaptic Terminals; Production; Proteins; Proton Pump Inhibitors; Publications; Publishing; Resolution; Sampling; Specificity; Structure; Surface; Synapses; Synaptic Transmission; Techniques; Technology; Temporal Lobe Epilepsy; Testing; Time; Transgenic Mice; Tyrosine; abeta accumulation; awake; carbon fiber; improved; in vivo; monomer; novel; oxidation; public health relevance; transmission process; voltage

DESCRIPTION (provided by applicant): Accumulation of A¿ plaque in the brain is a hallmark feature of Alzheimer's disease and a biomarker of disease progression. Observations in humans show that plaques are found in regions of the brain that display high levels of neuronal activity, sometimes referred to as the default mode network. Similarly, about 10% of individuals with temporal lobe epilepsy develop plaques within affected areas as early as 30 years of age. Studies from our lab have demonstrated that direct modulation of synaptic activity dynamically regulates brain A¿ levels in awake animals, with increased synaptic activity rapidly increases brain interstitial fluid (ISF) A¿ levels and vice versa for suppressed activity. These findings strongly suggest a close temporal relationship between synaptic activity and A¿ generation. Determining the mechanisms that underlie this link remains important for understanding the pathological development of AD. We have developed novel micro- immunoelectrode electrodes (MIEs) that detect A¿ with very high temporal resolution (measures A¿ in vivo every minute). This approach enables us to study the rapid kinetics and dynamics of A¿ in vivo. In our published studies (Prabhulkar et al. 2012), and in preliminary data we show that these MIEs can specifically measure ISF A¿1-40, A¿1-42 or aggregates, depending on the antibody attached to the electrode surface. Our in vivo MIE studies demonstrate brain interstitial fluid (ISF) A¿ levels change from minute-to-minute in APP/PS1 transgenic mice. Previous publications from our group and others demonstrate that ISF A¿ levels are closely linked to synaptic transmission. In vitro data suggest that high concentration and low pH facilitate conversion of A¿ into toxic aggregates. Synaptic activity increases A¿ generation within endosomes, a confined location where the pH is low, and the concentration of A¿ can potentially be elevated. We propose that there is a rapid link between synaptic transmission and A¿ generation, with higher frequencies of synaptic transmission causing more A¿ to be formed. In addition, elevated synaptic A¿ generation in low-pH endosomes will convert A¿ into aggregated species (either oligomers or fibrils). The goal of this proposal is to use this new MIE technology in combination with pharmacological manipulation to block or enhance specific aspects of synaptic activity to elucidate the cellular mechanisms that regulate A¿ generation and aggregation on a short time-scale. The results of these studies will improve our understanding of the temporal relationship between synaptic activity and A¿ generation/species and uncover mechanisms involved in the progression of AD.

描述（通过应用提供）：大脑中A斑块的积累是阿尔茨海默氏病的标志性特征，也是疾病进展的生物标志物。人类中的观察结果表明，在大脑的区域中发现了斑块，这些区域显示出高水平的神经元活动，有时也称为默认模式网络。同样，大约10％的患有暂时叶癫痫病的人早在30岁时就会在受影响地区内开发斑块。我们实验室的研究表明，突触活动的直接调节会动态调节醒着动物的大脑A水平，而突触活动的增加迅速增加了脑间隙液（ISF）A水平，反之亦然，以抑制活性。这些发现强烈表明合成活性与A的一代之间存在密切的临时关系。确定基于此链接的机制对于理解AD的病理发展仍然很重要。我们已经开发了新型的微免疫电极电极（MIES），该电极（MIES）以非常高的临时分辨率检测A e（每分钟都在体内测量A a。）。这种方法使我们能够研究体内a。的快速动力学和动力学。在我们发表的研究（Prabhulkar等人，2012年）中，在初步数据中，我们表明，这些MIES可以特异性地测量ISFa¿1-40，a¿1-42或骨料，具体取决于附着在电极表面上的抗体。我们的体内MIE研究表明大脑间隙液（ISF）A水平 在APP/PS1转基因小鼠中从分钟到分钟变化。我们小组和其他人的先前出版物表明，ISF A级别与突触传输密切相关。体外数据表明，高浓度和低pH值对a的转化为有毒骨料。突触活动在内体内增加了A a的生成，pH值较低，浓度可能会升高。我们建议，合成传递与A生成之间存在快速联系，突触传递的频率较高，导致更多的A形成。此外，低ph内体中的突触A升高将转化为聚集物种（低聚物或原纤维）。该提案的目的是将这种新的MIE技术与药物操纵结合使用，以阻止或增强突触活动的特定方面，以阐明在短时间内调节A生成和聚集的细胞机制。这些研究的结果将提高我们对合成活性与A的临时关系与A的生成/物种之间的暂时关系，并发现与AD进展有关的机制。